HIFU projects: The studies being carried out using high intensity focused ultrasound (HIFU) involve a unique variety of novel applications for drug delivery, cancer therapy, ablation, fibroid therapies, and thrombolysis. Building a foundation for these clinical applications necessitates directed pre-clinical safety and bridging studies that are requisite to bring drug-plus-device paradigms to clinical practice. The optimization of techniques and technologies for uterine fibroid image guided ablation is the first clinical trial for this technology at NIH CC, and was the first USA install of a new MRI-guided HIFU technology that uses MRI temperature maps to localize where the energy is deposited, with a real-time closed loop feedback algorithm that helps the physician prescribe and control the energy delivery. This novel technology is also delivered volumetrically and does not require linear sequential rastering, as does the predicate technology. Cavitation detection further improves the safety of this approach. The new clinical HIFU system can apply HIFU very rapidly, which mitigates the excessive time requirements for prior HIFU technologies, which was a major barrier to clinical translation. 1. Enhanced local drug deposition using low temperature sensitive liposomes (LTSLs): In preclinical models, we have shown that local doxorubicin delivery is enhanced in both tumors and muscle by combining systemic injections of LTSLs containing the drug and HIFU exposures. In the tumor studies, enhanced delivery was compared to non-thermo sensitive liposomes and shown to produce improved anti-tumor effects. Low energy HIFU exposures are tailored to generate temperature elevations that are just a few degrees Celsius above body temperature, which are non-destructive, and which cause a phase transition in the liposomes making them more permeable and able to release their payload. The image guided hyperthermia enhances permeability and perfusion as well. Presently, we are using a multi-disciplinary approach to optimize these treatments for improving spatial and temporal heating using computer simulations, in vitro experimentation, and in vivo studies. Collaborations with Dieter Haemmerich are developing a multi-parametric mathematical model that combines finite element analysis tools with perfusion modeling, tissue bioheat effects and known drug profiles to try to optimize the drug-plus-device approach prior to translation. Enhanced local drug deposition occurs through non-destructive and destructive mechanisms. Thermal ablation also deposits heat that adds to enhanced permeability and retention as well as mechanical deployment of heat-sensitive nanoparticles. Plans include phase I clinical trials for bone and soft tissue painful tumors. Preclinical work has focused on development of image-able nanoparticle agents that could theoretically define volumetric drug dosimetry. 2. Induced effects for enhancing immunotherapy of tumors: Various studies have shown that HIFU ablation can enhance adaptive immunity against tumors. It is hypothesized that in addition to destroying tumor tissue, tumor associated antigens are being released that can stimulate the immune system to create these effects. With NCI MOB collaborators, we published on the immunogenic effects of radiofrequency thermal ablation, and aim to study further translational opportunities to enhance immunotherapies for cancer. 3. Enhanced pharmacologic thrombolysis: HIFU and non focused ultrasound itself can enhance thrombolysis. We have shown that pre-treating whole blood clots with pulsed-HIFU can increase binding and penetration of tissue plasminogen activator (tPA) into the clots, and consequently improve rates of thrombolysis in vitro and in vivo. A novel thrombolysis model was developed and preclinical trials proved the augmentation of HIFU on thrombolysis in dialysis fistula grafts. 4. Safety: Studies on the safety and predictability of clinical HIFU exposures in the uterus (fibroids) with radiology - pathology correlation. HIFU exposures can produce a variety of effects for both adjunct and stand alone treatments. 5. Fibroid Ablation: Phase I clinical trial was completed for the use of MRI-guided Spiral volumetric closed loop feedback HIFU for the treatment of uterine fibroids as a pilot trial. 6. Cancer applications: Protocols to study HIFU for painful bone metastases as well as MRI-guided HIFU + heat deployed chemotherapy in a nanoparticle liposomal vector delivered IV, and a clinical trial for laparoscopically delivered HIFU for pancreatic cancer are being written. Devising a methodology for combining HIFU with other accepted interventional oncology regional and local therapies is the next step. Image-able liposomes that deploy chemotherapy have been shown in vivo to be able to deposit drug focally with image guidance, like a drug paintbrush.